The male hormone androgen has been known to have a close relationship with prostate cancer, benign prostatic hyperplasia, male pattern alopecia, precocious puberty, acne vulgaris, seborrhea and hypertrichosis. For example, it is known that castrated or hypogonadic patients rarely develop prostate cancer and benign prostatic hyperplasia.
As anti-androgen agents (i.e., antagonists against androgen receptor), various compounds are already used including cyproterone acetate, chlormadinone acetate, flutamide and bicalutamide. Cyproterone acetate is known to inhibit the progress of acne and the development of baldness in teenage patients. Cyproterone acetate is also used for the treatment of virilization and alopecia in female patients. Flutamide and bicalutamide are used as therapeutic agents for prostate cancer.
These anti-androgen agents are effective in many cases including drug therapy for prostate cancer and hence are regarded as one of the potent therapeutic agents. However, one of the problems with these anti-androgen agents is that in almost all cases, recurrences will occur, namely, androgen resistance develops, two to five years after the agents have proved effective on the disease.
Recently, hydroxyflutamide which is an active form of flutamide has been reported to enhance the transcriptional activity of androgen receptor at a concentration of 10 μmol/L. In addition, prostate cancer patients undergoing treatment with flutamide were reported to have blood hydroxyflutamide levels of several μmol/L which the report says corresponds to a concentration at which hydroxyflutamide showed its agonistic effects (see J. Biol. Chem., vol. 270, 19998–20003, 1995). There is also a report indicating that castrated rats continuously administered with cyproterone acetate and chlormadinone acetate for two weeks showed an increase in their prostate weight (Journal of Japan Endocrine Society, vol. 66, 597–606, 1990). Further, flutamide and bicalutamide were reported to have side effects such as liver toxicity.
On the other hand, an estrogen receptor antagonist is known as an example of a pure antagonist which serves as an antagonist against nuclear receptors without having agonistic effects, i.e., a substance which completely inhibits the action of the receptors (see, for example, WO98/25916, European Patent Publication No. 0138504, U.S. Pat. No. 4,659,516 and Cancer Res., 1991, 51, 3867). The molecular structures of hormone-binding domains in nuclear receptors such as RXR (retinoid-X receptor) and RAR (retinoic acid receptor) are being clarified by X-ray crystal structure analysis or other techniques (see, for example, Nature, vol. 375, 377–382, 1995).
WO97/49709 discloses an androgen receptor modulator comprising a non-steroidal tetracyclic compound.
Steroid compounds having an aminocarbonylalkyl group at position 7 or an aminocarbonylalkynyl group at position 17 are known from WO91/00732.
Steroid compounds having an aromatic ring or an alkyloxy group at position 11 are known from, for example, WO95/17192 which discloses RU486, a modifier for multiple drug resistance.
Also, compounds having various substituents at positions 7 and/or 11 are disclosed in the co-owned Japanese Patent Application Nos. Hei 11-274956 (filed on Aug. 23, 1999; hereinafter referred to as Application A) and Hei 11-338334 (filed on Oct. 22, 1999; hereinafter referred to as Application B).